Phthalazinone-piperidino-derivatives as PDE4 inhibitors

ABSTRACT

The compounds of formula I 
                         
in which the given substituents have the meanings as given in the description, are novel effective PDE4 inhibitors.

This application is a continuation of U.S. Ser. No. 10/467,832, filedAug. 13, 2003 now U.S. Pat. No. 6,953,853, which is a 371 ofPCT/EP02/01547, filed Feb. 14, 2002, the contents of which are herebyincorporated by reference in their entirety.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to novel piperidino-derivatives, which are used inthe pharmaceutical industry for the production of medicaments.

KNOWN TECHNICAL BACKGROUND

International Patent Applications WO98/31674 (=U.S. Pat. No. 6,103,718),WO99/31071, WO99/31090 and WO99/47505 (=U.S. Pat. No. 6,255,303)disclose phthalazinone derivatives having selective PDE4 inhibitoryproperties. In the International Patent Application WO94/12461 and inthe European Patent Application EP 0 763 534 3-aryl-pyridazin-6-one andarylalkyl-diazinone derivatives are described as selective PDE4inhibitors. International Patent Application WO93/07146 (=U.S. Pat. No.5,716,954) discloses benzo and pyrido pyridazinone and pyridazinthionecompounds with PDEIV inhibiting activity.

DESCRIPTION OF THE INVENTION

It has now been found that the piperidino-derivatives, which aredescribed in greater details below, have surprising and particularlyadvantageous properties.

The invention thus relates to compounds of formula I

in which

-   R1 and R2 are both hydrogen or together form an additional bond,-   R3 represents a benzene derivative of formula (a) or (b)

wherein

-   -   R4 is 1–4C-alkoxy or 1–4C-alkoxy which is completely or        predominantly substituted by fluorine,    -   R5 is 1–8C-alkoxy, 3–7C-cycloalkoxy, 3–7C-cycloalkylmethoxy, or        1–4C-alkoxy which is or predominantly substituted by fluorine,    -   R6 is 1–4C-alkoxy, 3–5C-cycloalkoxy, 3–5C-cycloalkylmethoxy, or        1–4C-alkoxy which is or predominantly substituted by fluorine,    -   R7 is 1–4C-alkyl and    -   R8 is hydrogen or 1–4C-alkyl,    -   or wherein    -   R7 and R8 together and with inclusion of the two carbon atoms,        to which they are bonded, form a spiro-linked 5-, 6- or        7-membered hydrocarbon ring, optionally interrupted by an oxygen        or sulphur atom,

-   R9 is 1–4C-alkyl, —S(O)₂—R10, —S(O)₂—(CH₂)_(n)—R11, —(CH₂)    _(m)−S(O)₂−R12, —C(O)R13, —C(O)—(CH₂)_(n)—R14, —(CH₂)_(m)—C(O)—R15,    Hetaryl, Aryl1 or 1–4C-alkyl-Aryl2,

-   R10 is 1–4C-alkyl, 5-dimethylaminonaphthalin-1-yl, —N(R16)R17,    phenyl or phenyl substituted by R18 and/or R19,

-   R11 is —N(R16)R17,

-   R12 is —N(R16)R17,

-   R13 is 1–4C-alkyl, hydroxycarbonyl-1–4C-alkyl, phenyl, pyridyl,    4-ethyl-piperazin-2,3-dion-1-yl or —N(R16)R17,

-   R14 is —N(R16)R17,

-   R15 is —N(R16)R17, phenyl, phenyl substituted by R18 and/or R19    and/or R20,

-   R16 and R17 are independent from each other hydrogen, 1–7C-alkyl,    3–7C-cycloalkyl, 3–7C-cycloalkylmethyl, phenyl or phenyl substituted    by R18 and/or R19 and/or R20, or R16 and R17 together and with    inclusion of the nitrogen atom to which they are bonded, form a    4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl-, 1-hexahydroazepino-    or a 1-piperazinyl-ring of formula (c)

-   -   wherein    -   R21 is pyrid-4-yl, pyrid-4-ylmethyl, 1–4C-alkyl-dimethylamino,        dimethylaminocarbonylmethyl, N-methyl-piperidin-4-yl,        4-morpholino-ethyl or tetrahydrofuran-2-ylmethyl,

-   R18 is halogen, nitro, cyano, carboxyl, 1–4C-alkyl, trifluoromethyl,    1–4C-alkoxy, 1–4C-alkoxycarbonyl, amino, mono-or di-1–4C-alkylamino,    aminocarbonyl 1–4C-alkylcarbonylamino or mono-or    di-1–4C-alkylaminocarbo

-   R19 is halogen, amino, nitro, 1–4C-alkyl or 1–4C-alkoxy,

-   R20 is halogen,

-   Hetaryl is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl,    1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl, thiazolyl, imidazolyl or    furanyl,

-   Aryl1 is pyridyl, phenyl or phenyl substituted by R18 and/or R19,

-   Aryl2 is pyridyl, phenyl, phenyl substituted by R18 and/or R19,    2-oxo-2H-chromen-7-yl or 4-(1,2,3-thiadiazol-4-phenyl,

-   n is an integer from 1 to 4,

-   m is an integer from 1 to 4,    and the salts of these compounds.

1–4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl,propyl, isopropyl, ethyl and methyl radicals.

1–4C-Alkoxy is a radical which, in addition to the oxygen atom, containsa straight-chain or branched alkyl radical having 1 to 4 carbon atoms.Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned inthis context are, for example, the butoxy, isobutoxy, sec-butoxy,tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.

1–8C-Alkoxy is a radical which, in addition to the oxygen atom, containsa straight-chain or branched alkyl radical having 1 to 8 carbon atoms.Alkoxy radicals having 1 to 8 carbon atoms which may be mentioned inthis context are, for example, the octyloxy, heptyloxy, isoheptyloxy(5-methylhexyloxy), hexyloxy, isohexyloxy (4-methylpentyloxy),neohexyloxy (3,3-dimethylbutoxy), pentyloxy, isopentyloxy(3-methylbutoxy), neopentyloxy (2,2-dimethylpropoxy), butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxyradicals.

Halogen within the meaning of the present invention is bromine, chlorineor fluorine.

3–7C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, of whichcyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

3–7C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy, cyclohexylmethoxy or cycloheptylmethoxy, of whichcyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy arepreferred.

3–5C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy andcyclopentyloxy.

3–5C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxyand cyclopentylmethoxy.

1–4C-Alkoxy which is completely or predominantly substituted by fluorineis, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy,the 1,2,2-trifluoroethoxy and in particular the1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, thetrifluoromethoxy and the difluoromethoxy radical, of which thedifluoromethoxy radical is preferred. “Predominantly” in this connectionmeans that more than half of the hydrogen atoms of the 1–4C-alkoxy groupare replaced by fluorine atoms.

As spiro-linked 5-, 6- or 7-membered hydrocarbon rings, optionallyinterrupted by an oxygen or sulphur atom, may be mentioned thecyclopentane, cyclohexane, cycloheptane, tetrahydrofuran,tetrahydropyran and the tetrahydrothiophen ring.

1–4C-Alkylcarbonyl is a carbonyl group to which one of theabovementioned 1–4C-alkyl radicals is bonded. An example is the acetylradical [CH₃C(O)—].

An 1–4C-Alkylcarbonylamino radical is, for example, the propionylamino[C₃H₇C(O)NH—] and the acetylamino radical [CH₃C(O)NH—].

Mono- or Di-1–4C-alkylamino radicals contain in addition to the nitrogenatom, one or two of the abovementioned 1–4C-alkyl radicals. Preferredare the di-1–4C-alkylamino radicals, especially the dimethylamino, thediethylamino and the diisopropylamino radical.

Mono- or Di-1–4C-alkylaminocarbonyl radicals contain in addition to thecarbonyl group one of the abovementioned mono- or di-1–4C-alkylaminoradicals. Examples which may be mentioned are the N-methyl- theN,N-dimethyl-, the N-ethyl-, the N-propyl-, the N,N-diethyl- and theN-isopropylaminocarbonyl radical.

Suitable salts for compounds of the formula I are all acid additionsalts. Particular mention may be made of the pharmacologically tolerableinorganic and organic acids customarily used in pharmacy. Those suitableare water-soluble and water-insoluble acid addition salts with acidssuch as, for example, hydrochloric acid, hydrobromic acid, phosphoricacid, nitric acid, sulphuric acid, acetic acid, citric acid, D-gluconicacid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid,sulphosalicylic acid, maleic acid, lauric acid, malic acid, fumaricacid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearicacid, toluenesulphonic acid, methanesulphonic acid or3-hydroxy-2-naphthoic acid, the acids being employed in saltpreparation—depending on whether a mono- or polybasic acid is concernedand depending on which salt is desired—in an equimolar quantitativeratio or one differing therefrom.

Pharmacologically intolerable salts, which can be obtained, for example,as process products during the preparation of the compounds according tothe invention on an industrial scale, are converted intopharmacologically tolerable salts by processes known to the personskilled in the art.

According to expert's knowledge the compounds of the invention as wellas their salts may contain, e.g. when isolated in crystalline form,varying amounts of solvents. Included within the scope of the inventionare therefore all solvates and in particular all hydrates of thecompounds of formula I as well as all solvates and in particular allhydrates of the salts of the compounds of formula I.

Compound of formula I to be emphasized are those in which

-   R1 and R2 are both hydrogen or together form an additional bond,-   R3 represents a benzene derivative of formula (a) or (b)

wherein

-   -   R4 is 1–4C-alkoxy or 1–2C-alkoxy which is completely or        predominantly substituted by fluorine,    -   R5 is 1–4C-alkoxy,    -   R6 is 1–2C-alkoxy or 1–2C-alkoxy which is completely or        predominantly substituted by fluorine,    -   R7 is methyl and    -   R8 is hydrogen,    -   or wherein    -   R7 and R8 together and with inclusion of the two carbon atoms,        to which they are bonded, form a spiro-linked cyclopentane,        cyclohexane, tetrahydrofurane or tetrahydropyran ring,

-   R9 is 1–4C-alkyl, —S(O)₂—R10, —S(O)₂—(CH₂)_(n)—R11,    —C(O)R13,—C(O)—(CH₂)_(n)—R14, —(CH₂)_(m)—C(O)—R15, Hetaryl, Aryl1 or    1–2C-alkyl-Aryl2,

-   R10 is 1–4C-alkyl, 5-dimethylaminonaphthalin-1-yl, —N(R16)R17,    phenyl or phenyl substituted by R18,

-   R11 is —N(R16)R17,

-   R13 is 1–4C-alkyl, hydroxycarbonyl-1–4C-alkyl, phenyl, pyridyl,    4-ethyl-piperazin-2,3-dion-1-yl or —N(R16)R17,

-   R14 is —N(R16)R17,

-   R15 is —N(R16)R17, phenyl, phenyl substituted by R18 and/or R19    and/or R20,

-   R16 and R17 are independent from each other hydrogen, 1–4C-alkyl,    phenyl or phenyl substituted by R18 and/or R19 and/or R20, or R16    and R17 together and with inclusion of the nitrogen atom to which    they are bonded, form a 4-morpholinyl ring, a 1-piperidinyl ring or    a 1-piperazinyl ring of formula (c)

-   -   wherein    -   R21 is pyrid-4-yl, pyrid-4-ylmethyl, dimethylamino-1–4C-alkyl,        dimethylaminocarbonylmethyl, N-methyl-piperidin-4-yl,        4-morpholino-ethyl or tetrahydrofuran-2-ylmethyl,

-   R18 is halogen, nitro, 1–4C-alkyl, trifluoromethyl, 1–4C-alkoxy or    1–4C-alkoxycarbonyl,

-   R19 is halogen, amino, nitro, 1–4C-alkyl or 1–4C-alkoxy,

-   R20 is halogen,

-   Hetaryl is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl or    1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl,    -   Aryl1 is pyridyl, phenyl or phenyl substituted by R18,    -   Aryl2 is pyridyl, phenyl, phenyl substituted by R18,        2-oxo-2H-chromen-7-yl or 4-(1,2,3-thiadiazol-4-yl)phenyl,

-   n is 1 or 2,

-   m is 1 or 2,    and the salts of these compounds.

Preferred compounds of formula I are those, in which

-   R1 and R2 together form an additional bond,-   R3 represents a benzene derivative of formula (a) or (b)

wherein

-   -   R4 is 1–4C-alkoxy,    -   R5 is 1–4C-alkoxy,    -   R6 is 1–2C-alkoxy,    -   R7 is methyl and    -   R8 is hydrogen,

-   R9 is 1–4C-alkyl, —S(O)₂—R10, —C(O)R13, —C(O)—(CH₂)_(n)—R14,    —(CH₂)_(m)—C(O)—R15, Heteryl, Aryl1 or 1–2C-alkyl-Aryl2,

-   R10 is 1–4C-alkyl, 5-dimethylaminonaphthalin-1-yl, phenyl or phenyl    substituted by R18,

-   R13 is 1–4C-alkyl, hydroxycarbonyl-1–4C-alkyl, pyridyl,    4-ethyl-piperazin-2,3-dion-1-yl or —N(R16)R17,

-   R14 is —N(R16)R17,

-   R15 is —N(R16)R17, phenyl or phenyl substituted by R18 and/or R19    and/or R20,

-   R16 and R17 are independent from each other hydrogen, 1–4C-alkyl,    phenyl or phenyl substituted by R18 and/or R19 and/or R20, or R16    and R17 together and with inclusion of the nitrogen atom to which    they are bonded, form a 4-morpholinyl ring or a 1-piperazinyl ring    of formula (c)

-   -   wherein    -   R21 is dimethylamino-1–4C-alkyl,

-   R18 is halogen, nitro, 1–4C-alkyl or 1–4C-alkoxycarbonyl,

-   R19 is amino,

-   R20 is halogen,

-   Hetaryl is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl or    1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl,

-   Aryl1 is phenyl or phenyl substituted by R18,

-   Aryl2 is pyridyl, phenyl, 2-oxo-2H-chromen-7-yl or    4-(1,2,3-thiadiazol-4-yl)phenyl,

-   n is 1 or 2,

-   m is 1 or 2,    and the salts of these compounds.

Particularly preferred compounds of formula I are those In which

-   R1 and R2 together form an additional bond,-   R3 represents a benzene derivative of formula (a) or (b)

wherein

-   -   R4 is methoxy or ethoxy,    -   R5 is methoxy or ethoxy,    -   R6 is methoxy or ethoxy,    -   R7 is methyl and    -   R8 is hydrogen,

-   R9 is toluene-4-sulfonyl, methanesulfonyl, acetyl, 5-oxo-pentanoic    acid, pyridin-4-yl-carbonyl, tert-butylaminocarbonyl,    phenylaminocarbonyl, 5-dimethylamino-naphthalene-1-sulfonyl,    4-nitrophenyl, pyridin-4-ylmethyl, morpholine-4-carbonyl,    2-(4-amino-3,5-dichlorophenyl)-2-oxo-ethyl,    1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl,    thieno[2,3-d]pyrimidin-4-yl, pyrimidin-2-yl,    2-oxo-2H-chromen-7-ylmethyl, isopropyl, morpholin-4-yl-2-oxo-ethyl,    phenethyl, pyridin-3-ylmethyl, pyridin-2-ylmethyl,    pyridin-4-ylmethyl, 2-morpholin-4-ylethanoyl,    2-[4-(2-dimethylaminoethyl)-piperazin-1-yl]-ethanolyl,    isopropylaminocarbonylmethyl,    4-ethyl-piperazine-2,3-dione-1-carbonyl,    4-(1,2,3-thiadiazol-4-yl-)benzyl,    4-ethoxycarbonylphenylamino-2-oxo-ethyl or aminocarbonylmethyl,    and the salts of these compounds.

The compounds of formula I are chiral compounds. Chiral centers exist inthe compounds of formula I in the positions 4a and 8a. In case R3represents a benzene derivative of formula (b) there is one furtherchiral center in the dihydrofuran-ring, If the substituents —R7 and—CH₂R8 are not identical. However, preferred are in this connectionthose compounds, in which the substituents —R7 and —CH₂R8 are identicalor together and with inclusion of the two carbon atoms to which they arebonded form a spiro-connected 5-, 6- or 7-membered hydrocarbon ring.

Therefore the invention includes all conceivable pure diastereomers andpure enantiomers of the compounds of formula I, as well as all mixturesthereof independent from the ratio, including the racemates. Preferredare those compounds of formula I, in which the hydrogen atoms in thepositions 4a and 8a are cis-configurated. Especially preferred in thisconnection are those compounds, in which the absolute configuration(according to the rules of Cahn, Ingold and Prelog) is S in the position4a and R in the position 8a. Racemates can be split up into thecorresponding enantiomers by methods known by a person skilled in theart. Preferably the racemic mixtures are separated into twodiastereomers during the preparation with the help of an optical activeseparation agent on the stage of the cyclohexane-carboxylic acids or the1,2,3,6-tetrahydrobenzoic acids (for example, starting compounds A1, A2and A3). As separation agents may be mentioned, for example, opticalactive amines such as the (+)- and (−)-forms of 1-phenylethylamine[(R)-(+)-1-phenylethylamine=(R)-(+)-α-methylbenzylamine or(S)-(−)-1-phenylethylamine=(S)-(−)-α-methylamine) and epehedrine, theoptical active alkaloids quinine, cinchonine, cinchonidine and brucine.

The compounds according to the invention can be prepared, for example,as described in Reaction scheme 1.

Reaction scheme 1 shows that the compounds of formula I can be, forexample, prepared starting from 4-oxo-piperidine-1-carboxylic acidtert-butyl ester which is reacted in a first reaction step withtert-butylcarbazate to give4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acidtert-butyl ester (starting compound A7). Compound A7 is reduced with,for example, the boran tetrahydrofurane complex to give4-(N′-tert-Butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acidtert-butyl ester (starting compound A6). Treatment of compound A6 withconcentrated hydrochloric acid results in the formation ofpiperidin-4-yl-hydrazine dihydrochloride (starting compound A5).

The reaction of piperidin-4-yl-hydrazine dihydrochloride withcyclohexanecarboxylic acids or 1,2,3,6-tetrahydrobenzoic acids offormulae IIIa or IIIb leads to the piperidino derivatives of formula II.

These are reacted in the final reaction step with compounds of formulaR9—X, wherein X represents a suitable leaving group, preferably achlorine atom, to give the compounds of formula I.

For some compounds of formula I, it can be advantageous, to introducethe substituent R9 in two reaction steps. As example may be mentionedthose compounds of formula I, wherein R9 representsmorpholin-4-ylethanoyl. Here, the corresponding compounds of formula IIare reacted in a first step with chloroacetylchloride and then in asecond step with morpholine.

Suitably, the conversions are carried out analogous to methods which arefamiliar per se to the person skilled in the art, for example, in themanner which is described in the following examples.

The preparation of the cyclohexanecarboxylic acids and1,3,5,6-tetrahydrobenzoic acids of the formulae IIIa or IIIb isdescribed, for example, in WO98/31674, WO99/31090 and WO99/47505.

The substances according to the invention are isolated and purified in amanner known per se, e.g. by distilling off the solvent in vacuo andrecrystallising the residue obtained from a suitable solvent orsubjecting it to one of the customary purification methods, such ascolumn chromatography on a suitable support material.

Salts are obtained by dissolving the free compound in a suitable solvent(for example a ketone like acetone, methylethylketone, ormethylisobutylketone, an ether, like diethyl ether, tetrahydrofuran ordioxane, a chlorinated hydrocarbon, such as methylene chloride orchloroform, or a low molecular weight aliphatic alcohol, such asethanol, isopropanol) which contains the desired acid, or to which thedesired acid is then added. The salts are obtained by filtering,reprecipitating, precipitating with a non-solvent for the addition saltor by evaporating the solvent. Salts obtained can be converted bybasification into the free compounds which, in turn, can be convertedInto salts. In this manner, pharmacologically non-tolerable salts can beconverted into pharmacologically tolerable salts.

The following examples illustrate the invention in greater detail,without restricting it. As well, further compounds of formula I, ofwhich the preparation is explicitly not described, can be prepared in ananalogous way or in a way which is known by a person skilled in the artusing customary preparation methods.

The compounds, which are mentioned in the examples as well as theirsalts are preferred compounds of the invention.

EXAMPLES

Final Products

-   1.    (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,    5,8,8a-tetraphydro-2H-phthalazin-1-one

A solution of 1.0 g of starting compound A2 and 1.0 g ofp-toluenesulfonyl chloride in 50 ml of pyridine is stirred at RT for 18h after which the mixture is evaporated. The residue is partitionedbetween aqueous sodium carbonate and dichloromethane. Thedichloromethane layer is dried over magnesium sulfate and evaporated.The compound is crystallised from methanol. M. p. 99–101° C.

-   2.    (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetraphydro-2h-    phthalazin-1-one

Prepared from methanesulfonylchloride and starting compound A2 asdescribed for compound 1. Crystallisation from methanol/water. M. p.99–102° C.

-   3.    (4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from acetic anhydride and starting compound A2 as described forcompound 1. Crystallised from diethyl ether. M. p. 148–150° C.

-   4.    5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoic    acid

Prepared from glutaric anhydride and starting compound A2 as describedfor compound 1. After evaporating the pyridine, the residue ispartitioned between ethyl acetate and 1N hydrochloric acid. The ethylacetate solution is dried over magnesium sulfate and evaporated.Crystallisation from diethyl ether. M. p. 133–135° C.

-   5.    (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    hydrochloride

Prepared from isonicotinoyl chloride hydrochloride and starting compoundA2 as described for compound 1. After evaporating the dichloromethanesolution, the residue is dissolved in diethyl ether. After addition of asaturated solution of hydrochloric acid in ether, the titel compoundprecipitates. M. p. 66–68° C.

-   6.    4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-carboxylic    acid tert-butylmide acid tert-butylamide

A mixture of 1.0 g of starting compound A2, 0.5 g of t-butylisocyanateand 2 ml of triethylamine in 50 ml of tetrahydrofurane is stirred for 18h at RT. After evaporating the solution, the residue is partitionedbetween water and ethyl acetate. Crystallisation from a mixture ofdichloromethane and petroleum ether (60–80° C.). M. p. 145–148° C.

-   7.    4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1    -carboxylic acid phenylamide acid phenylamide

Prepared from starting compound A2 and phenylisocyanate as described forcompound 6. Crystallisation from ether. M. p. 109–112° C.

-   8.    4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid tert-butylamide

Prepared from starting compound A1 and t-butylisocyanate as describedfor compound 6. Crystallisation from ether. M. p. 164–166° C.

-   9.    (cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxyylic    acid tert-butylamide

Prepared from starting compound A3 and t-butylisocyanate as describedfor compound 6. Crystallisation from ether. M. p. 145–147° C.

-   10.    (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydyro-2H-phthalazin-1-one

Prepared from dansylchloride and starting compound A1 as described forcompound 1. Crystallisation from methanol. M. p. 198–200° C.

-   11.    (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

A mixture of 1.0 g of compound A1, 1.0 g of 1-iodo-4-nitrobenzene and1.0 g of potassium carbonate in 20 ml of dimethylformamide is stirredfor 18 h at RT after which 100 ml of water Is added to the reactionmixture. The precipitate is filtered off and crystallised from methanol.M. p. 196–197° C.

-   12.    (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8,a-tetrahydro-2H-phthalazin-1-one

Prepared from starting compound A1 and 4-picolylchloride hydrochlorideas described for compound 11. After the addition of 100 ml of water, 20ml of diethyl ether is added and the resulting mixture stirred for 30min. The precipitate is filtered off and dried. M. p. 196–197° C.

-   13.    (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from 4-morpholinocarbonyl chloride and compound A1 as describedfor compound 1. Crystallisation from diethyl ether. M. p. 184–185° C.

-   14.    (4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    hydrochloride

Prepared from (4-Amino-3,5-dichloro-phenyl)-2-bromo-ethanone andstarting compound A1 as described for compound 11. After the addition ofwater, the mixture is extracted with diethyl ether. The ether solutionis dried over magnesium sulfate. After the addition of a saturatedsolution of hydrochloric acid in ether, the compound precipitates.Crystallisation from tetrahydrofurane. M. p. 206° C. (decomposition).

-   15.    4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one

Prepared from 4-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine and startingcompound A1 as described for compound 11. Crystallisation from methanol.M. p. 193–194° C.

-   16.    (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from 4-Chloro-thieno[2,3-d]pyrimidine and starting compound A1as described for compound 11. After the addition of water, the mixtureis extracted with diethyl ether. The ether solution is dried overmagnesium sulfate. After the addition of a saturated solution ofhydrochloric acid in ether, the compound precipitates. M. p. 219–220° C.

-   17.    (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from 2-Chloro-pyrimidine and starting compound A1 as describedfor compound 11. Crystallisation from methanol. M. p. 163–166° C.

-   18.    (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    hydrochloride

Prepared from 7-Chloromethyl-chromen-2-one and starting compound A1 asdescribed for compound 11. After the addition of water, the mixture isextracted with diethyl ether. The ether solution is dried over magnesiumsulfate. After the addition of a saturated solution of hydrochloric acidin ether, the compound precipitates. M. p. 264–267° C.

-   19.    4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    hydrochloride

Prepared from 2-iodopropane and starting compound A1 as described forcompound 18. M. p. 158–159° C.

-   20.    (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    hydrochloride

Prepared from 4-(2-chloroacetyl)morpholine and starting compound A1 asdescribed for compound 18. M. p. 159–162° C.

-   21.    (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    hydrochloride

Prepared from 2-bromoethylbenzene and starting compound A1 as describedfor compound 18. M. p. 216–217° C.

-   22.    (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from 4-morpholinocarbonyl chloride and starting compound A2 asdescribed for compound 1. Crystallisation from diethyl ether. M. p.139–141° C.

-   23.    (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    dihydrochloride

Prepared from starting compound A1 and 3-picolylchloride hydrochlorideas described for compound 18. M. p. 252–254° C.

-   24.    (4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    dihydrochloride

Prepared from compound A1 and 2-picolylchloride hydrochloride asdescribed for compound 18. M. p. 214–216° C.

-   25.    (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    hydrochloride

Prepared from starting compound A5 and morpholine as described forcompound 18. M. p. 219° C. (decomposition).

-   26.    (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl)-piperidin-1-yl]-ethanoyl}-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    trihydrochloride

Prepared from starting compound A4 anddimethyl-(2-piperazin-1-yl-ethyl)-amine as described for compound 18. M.p. 195–197° C.

-   27.    2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-isopropyl-acetamide

Prepared from starting compound A1 and N-(chloroacetyl)isopropylamine asdescribed for compound 11. Crystallisation from ether. M. p. 172–173° C.

-   28.    (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    dihydrochloride

Prepared from starting compound A1 and4-(4-Bromomethyl-phenyl)-[1,2,3]thiadiazole as described for compound18. M. p. 243–245° C.

-   29.    1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-methanoyl)-4-ethyl-piperazine-2,3-dione

Prepared from 4-ethyl-2,3-dioxo-piperazine-1-carbonyl chloride andstarting compound A1 as described for compound 1. Crystallisation fromethyl acetate/diethyl ether. M. p. 226–228° C.

-   30.    4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)-benxzoic    acid ethyl acid ethyl ester hydrochloride

Prepared from ethyl 4-(2-chloroacetamido)benzoate and starting compoundA1 as described in example 18. M. p. 153–156° C.

-   31. 2-{4-[(4aS,8aR)-4-(3,4-Dimethoxphenyl)-1-oxo-4a,    5,8,8a-tetrahyro-1H-phthalazin-2-yl]-piperidin-1-yl}-acetamide    hydrochloride

Prepared from 2-chloroacetamide and starting compound A1 as describedfor compound 16. M.p. 241–243°C.

Starting Compounds

-   A1.    (4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    hydrochloride

A solution of 50 mmol of the salt of (S)-(−)-α-methylbenzylamine and(cis)-2-(3,4-dimethoxybenzoyl)-1,2,3,6-tetrahydrobezoic acid (startingcompound A8), 55 mmol of piperidin-4-yl-hydrazine dihydrochloride and100 mmol of triethylamine in 150 ml of 1-propanol is refluxed for 18 h.After cooling to RT, the precipitate is filtered off and dried. M. p.285–288° C.

-   A2.    (4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    hydrochloride

Prepared from the salt of (S)-(−)-α-methylbenzylamine and(cis)-2-(3,4-diethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid (startingcompound A9) in 2-propanol as described for compound A1. M. p. 248–250°C.

-   A3.    (cis)-4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    hydrochloride

Prepared from (cis)-2-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4carbonyl)-1,2,3,6-tetrahydro benzoic acid (starting compound A10) in1-propanol as described for compound A1. After evaporating the solvent,the residue is partitioned between dichloromethane and aqueous sodiumcarbonate. The dichlormethane layer is dried over magnesium sulfate andevaporated. The residue is dissolved in dichloromethane and after theaddition of a solution of hydrochloric acid in ether, the compoundprecipitates. M. p. 288–290° C.

-   A4.    (4aS,8aR)-2-[1-(2-Chloro-acetyl)-piperidin-4-yl]-4-(3,4-diethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

A solution of 15 mmol of chloroacetylchloride in 10 ml ofdichloromethane is added to a solution of 15 mmol of starting compoundA2 and 8 ml of trietylamine in 50 ml of dichloromethane at 0° C. Aftercomplete addiotion, the mixture is stirred for another 45 min afterwhich 50 ml of water is added. The dichlormethane solution is dried overmagnesium sulfate and evaporated. The residue is purified bychromatography. Elution with a 2/1 mixture of ethyl acetate andpetroleum ether (60–80° C.). Crystallisation from hexane. M. p. 135–136°C.

-   A5. Piperidin-4-yl-hydrazine dihydrochloride

A mixture of 0.1 mole of4-(N′-tert-Butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acidtert-butyl ester (starting compound A6) and 150 ml of concentratedhydrochloric acid is heated at 90° C. for 60 min after which the clearsolution is evaporated. The residue is washed with tetrahydrofurane,filtered off and dried under vacuum. M. p. 256–259° C.

-   A6. 4-(N′-tert-Butoxycarbonyl-hydrazino)-piperidine-1-carboxylic    acid tert-butyl ester

150 ml of a solution of borohydride in tertahydrofurane (1.0 mol/l) isslowly added to a solution of 0.12 mole of4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acidtert-butyl ester (starting compound A7) in 100 ml of drytetrahydrofurane. After complete addition, the mixture is stirred foranother 30 min after which a 100 ml of water is added to destroy theexcess of borohydride. Subsequently the tetrahydrofurane is evaporatedand the resulting aqeous solution extracted with diethyl ether. Afterdrying the solvent over magnesium sulfate, the ether is evaporated. M.p. 112–115° C.

-   A7. 4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acid    tert-butyl ester

A mixture of 0.15 mole of 4-oxo-piperidine-1-carboxylic acid tert-butylester (commercially available) and 0.15 mole of tert-butylcarbazate in250 ml of hexane is stirred for 18 h at RT. The precipitate is filteredoff and dried under vacuum. M. p. 172–174° C.

-   A8. (cis)-2-(3,4-Dimethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid

Prepared as described in WO98/31674.

-   A9. (cis)-2-(3,4-diethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid

Prepared as described in WO99/47505.

-   A10.    (cis)-2-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-carbonyl)-1,2,3,6-tetrahydrobenzoic    acid

Prepared as described in WO99/31090.

Commercial Utility

The compounds according to the invention have useful pharmacologicalproperties which make them industrially utilizable. As selective cyclicnucleotide phosphodiesterase (PDE) inhibitors (specifically of type 4),they are suitable on the one hand as bronchial therapeutics (for thetreatment of airway obstructions on account of their dilating action butalso on account of their respiratory rate- or respiratorydrive-increasing action) and for the removal of erectile dysfunction onaccount of their vascular dilating action, but on the other handespecially for the treatment of disorders, in particular of aninflammatory nature, e.g. of the airways (asthma prophylaxis), of theskin, of the intestine, of the eyes, of the CNS and of the joints, whichare mediated by mediators such as histamine, PAF (platelet-activatingfactor), arachidonic acid derivatives such as leukotrienes andprostaglandins, cytokines, interleukins, chemokines, alpha-, beta- andgamma-interferon, tumor necrosis factor (TNF) or oxygen free radicalsand proteases. In this context, the compounds according to the Inventionare distinguished by a low toxicity, a good enteral absorption (highbioavailability), a large therapeutic breadth and the absence ofsignificant side effects.

On account of their PDE-inhibiting properties, the compounds accordingto the invention can be employed in human and veterinary medicine astherapeutics, where they can be used, for example, for the treatment andprophylaxis of the following illnesses: acute and chronic (in particularinflammatory and allergen-induced) airway disorders of varying origin(bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD);dermatoses (especially of proliferative, inflammatory and allergic type)such as psoriasis (vulgaris), toxic and allergic contact eczema, atopiceczema, seborrhoeic eczema, Lichen simplex, sunburn, pruritus in theanogenital area, alopecia areata, hypertrophic scars, discoid lupuserythematosus, follicular and widespread pyodermias, endogenous andexogenous acne, acne rosacea and other proliferative, inflammatory andallergic skin disorders; disorders which are based on an excessiverelease of TNF and leukotrienes, for example disorders of the arthritistype (rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis andother arthritic conditions), disorders of the immune system (AIDS,multiple sclerosis), graft versus host reaction, allograft rejections,types of shock (septic shock, endotoxin shock, gram-negative sepsis,toxic shock syndrome and ARDS (adult respiratory distress syndrome)) andalso generalized inflammations in the gastrointestinal region (Crohn'sdisease and ulcerative colitis); disorders which are based on allergicand/or chronic, immunological false reactions in the region of the upperairways (pharynx, nose) and the adjacent regions (paranasal sinuses,eyes), such as allergic rhinitis/sinusitis, chronic rhinitis/sinusitis,allergic conjunctivitis and also nasal polyps; but also disorders of theheart which can be treated by PDE inhibitors, such as cardiacinsufficiency, or disorders which can be treated on account of thetissue-relaxant action of the PDE inhibitors, such as, for example,erectile dysfunction or colics of the kidneys and of the ureters inconnection with kidney stones. In addition, the compounds of theinvention are useful in the treatment of diabetes insipidus andconditions associated with cerebral metabolic inhibition, such ascerebral senility, senile dementia (Alzheimer's disease), memoryimpairment associated with Parkinson's disease or multiinfarct dementia;and also illnesses of the central nervous system, such as depressions orarteriosclerotic dementia.

The invention further relates to a method for the treatment of mammals,including humans, which are suffering from one of the above mentionedillnesses. The method is characterized in that a therapeutically activeand pharmacologically effective and tolerable amount of one or more ofthe compounds according to the invention is administered to the illmammal.

The invention further relates to the compounds according to theinvention for use in the treatment and/or prophylaxis of illnesses,especially the illnesses mentioned.

The invention also relates to the use of the compounds according to theinvention for the production of medicaments which are employed for thetreatment and/or prophylaxis of the illnesses mentioned.

The invention furthermore relates to medicaments for the treatmentand/or prophylaxis of the illnesses mentioned, which contain one or moreof the compounds according to the invention.

Additionally, the invention relates to an article of manufacture, whichcomprises packaging material and a pharmaceutical agent contained withinsaid packaging material, wherein the pharmaceutical agent istherapeutically effective for antagonizing the effects of the cyclicnucleotide phosphodiesterase of type 4 (PDE4), ameliorating the symptomsof an PDE4-mediated disorder, and wherein the packaging materialcomprises a label or package insert which indicates that thepharmaceutical agent is useful for preventing or treating PDE4-mediateddisorders, and wherein said pharmaceutical agent comprises one or morecompounds of formula I according to the invention. The packagingmaterial, label and package insert otherwise parallel or resemble whatis generally regarded as standard packaging material, labels and packageinserts for pharmaceuticals having related utilities.

The medicaments are prepared by processes which are known per se andfamiliar to the person skilled in the art. As medicaments, the compoundsaccording to the invention (=active compounds) are either employed assuch, or preferably in combination with suitable pharmaceuticalauxiliaries, e.g. in the form of tablets, coated tablets, capsules,suppositories, patches, emulsions, suspensions, gels or solutions, theactive compound content advantageously being between 0.1 and 95%.

The person skilled in the art is familiar with auxiliaries which aresuitable for the desired pharmaceutical formulations on account of hisexpert knowledge. In addition to solvents, gel formers, ointment basesand other active compound excipients, for example antioxidants,dispersants, emulsifiers, preservatives, solubilizers or permeationpromoters, can be used.

For the treatment of disorders of the respiratory tract, the compoundsaccording to the invention are preferably also administered byinhalation in the form of an aerosol; the aerosol particles of solid,liquid or mixed composition preferably having a diameter of 0.5 to 10μm, advantageously of 2 to 6 μm.

Aerosol generation can be carried out, for example, by pressure-drivenjet atomizers or ultrasonic atomizers, but advantageously bypropellant-driven metered aerosols or propellant-free administration ofmicronized active compounds from inhalation capsules.

Depending on the inhaler system used, in addition to the activecompounds the administration forms additionally contain the requiredexcipients, such as, for example, propellants (e.g. Frigen in the caseof metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, flavorings, fillers (e.g. lactose in thecase of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of apparatuses areavailable with which aerosols of optimum particle size can be generatedand administered, using an inhalation technique which is as right aspossible for the patient. In addition to the use of adaptors (spacers,expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), andautomatic devices emitting a puffer spray (Autohaler®), for meteredaerosols, in particular in the case of powder inhalers, a number oftechnical solutions are available (e.g. Diskhaler®, Rotadisk®,Turbohaler® or the inhaler described in European Patent Application EP 0505 321), using which an optimal administration of active compound canbe achieved.

For the treatment of dermatoses, the compounds according to theinvention are in particular administered in the form of thosemedicaments which are suitable for topical application. For theproduction of the medicaments, the compounds according to the invention(=active compounds) are preferably mixed with suitable pharmaceuticalauxiliaries and further processed to give suitable pharmaceuticalformulations. Suitable pharmaceutical formulations are, for example,powders, emulsions, suspensions, sprays, oils, ointments, fattyointments, creams, pastes, gels or solutions.

The medicaments according to the invention are prepared by processesknown per se. The dosage of the active compounds is carried out in theorder of magnitude customary for PDE inhibitors. Topical applicationforms (such as ointments) for the treatment of dermatoses thus containthe active compounds in a concentration of, for example, 0.1–99%. Thedose for administration by inhalation is customarly between 0.1 and 3 mgper day. The customary dose in the case of systemic therapy (p.o. ori.v.) is between 0.03 and 3 mg/kg per day.

Biological Investigations

The second messenger cyclic AMP (cAMP) is well-known for inhibitinginflammatory and immunocompetent cells. The PDE4 isoenzyme is broadlyexpressed in cells involved in the initiation and propagation ofinflammatory diseases (H Tenor and C Schudt, in “PhosphodiesteraseInhibitors”, 21–40, “The Handbook of Immunopharmacology”, AcademicPress, 1996), and its inhibition leads to an increase of theintracellular cAMP concentration and thus to the inhibition of cellularactivation (J E Souness et al., Immunopharmacology 47: 127–162, 2000).

The antiinflammatory potential of PDE4 inhibitors in vivo in variousanimal models has been described (MM Teixeira, TiPS 18: 164–170, 1997).For the investigation of PDE4 inhibition on the cellular level (invitro), a large variety of proinflammatory responses can be measured.Examples are the superoxide production of neutrophilic (C Schudt et al.,Arch Pharmacol 344: 682–690, 1991) or eosinophilic (A Hatzelmann et al.,Brit J Pharmacol 114: 821–831, 1995) granulocytes, which can be measuredas luminol-enhanced chemiluminescence, or the synthesis of tumornecrosis factor-α in monocytes, macrophages or dendritic cells (Gantneret al., Brit J Pharmacol 121: 221–231, 1997, and Pulmonary PharmacolTherap 12: 377–386, 1999). In addition, the immunomodulatory potentialof PDE4 inhibitors is evident from the inhibition of T-cell responseslike cytokine synthesis or proliferation (D M Essayan, Biochem Pharmacol57: 965–973, 1999). Substances which inhibit the secretion of theafore-mentioned proinflammatory mediators are those which inhibit PDE4.PDE4 inhibition by the compounds according to the invention is thus acentral indicator for the suppression of inflammatory processes.

Method for Measuring Inhibition of PDE4 Activity

PDE4 activity was determined as described by Thompson et al. (Adv CyclNucl Res 10: 69–92, 1979) with some modifications (Bauer and Schwabe,Naunyn-Schmiedeberg's Arch Pharmacol 311: 193–198, 1980). At a finalassay volume of 200 μl (96 well microtiter plates) the assay mixturecontained 20 mM Tris (pH 7.4), 5 mM MgCl₂, 0.5 μM cAMP, [³H]cAMP (about30,000 cpm/assay), the test compound and an aliquot of cytosol fromhuman neutrophils which mainly contains PDE4 activity as described bySchudt et al. (Naunyn-Schmiedeberg's Arch Pharmacol 344: 682–690, 1991);the PDE3-specific inhibitor Motapizone (1 μM) was included to suppressPDE3 activity originating from contaminating platelets. Serial dilutionsof the compounds were prepared in DMSO and further diluted 1:100 (v/v)in the assays to obtain the desired final concentrations of theinhibitors at a DMSO concentration of 1% (v/v) which by itself onlyslightly affected PDE4 activity.

After preincubation for 5 min at 37° C., the reaction was started by theaddition of substrate (cAMP) and the assays were incubated for further15 min at 37° C. 50 μl of 0.2 N HCl was added to stop the reaction andthe assays were left on ice for about 10 min. Following incubation with25 μg 5′-nucleotidase (Crotalus atrox snake venom) for 10 min at 37° C.,the assays were loaded on QAE Sephadex A-25 (1 ml bed volume). Thecolumns were eluted with 2 ml of 30 mM ammonium formuiate (pH 6.0) andthe eluate was counted for radioactivity. Results were corrected forblank values (measured in the presence of denatured protein) which werebelow 5% of total radioactivity. The amount of cyclic nucleotideshydrolyzed did not exceed 30% of the original substrate concentration.The IC₅₀-values for the compounds according to the invention for theinhibition of the PDE4 activity were determined from theconcentration-inhibition curves by nonlinear-regression.

The inhibitory values determined for the compounds according to theinvention follow from the following table A, in which the numbers of thecompounds correspond to the numbers of the examples.

TABLE A Inhibition of PDE4 acitivity [measured as −logIC₅₀ (mol/l)]compound −logIC₅₀ 7 10.28 8 10.18 9 10.65 10 9.57 11 10.34 12 10.79 1310.03 14 10.33 15 10.27 16 10.50 17 10.51 18 10.32 20 10.40 21 9.69 229.37 23 10.80 24 10.63 25 10.19 27 10.37 28 10.24 29 10.87 31 9.20

1. A compound of formula I

in which R1 and R2 are both hydrogen or together form an additionalbond, R3 represents a benzene derivative of formula (a)

wherein R4 is 1–4C-alkoxy, R5 is 1–8C alkoxy, R9 is (CH₂)_(m)—C(O)—R15,wherein R15 is —N(R16)R17, R16 and R17 are independent from each otherand are hydrogen or 1–7C-alkyl, and m is an integer from 1 to 4, or ahydrate, salt or hydrate of a salt thereof.
 2. A compound of formula Iaccording to claim 1 or a hydrate, salt or hydrate of a salt thereof, inwhich the hydrogen atoms in the positions 4a and 8a arecis-configurated.
 3. A compound of formula I according to claim 1 or ahydrate, salt or hydrate of a salt thereof, in which the absoluteconfiguration is S in the position 4a and R in the position 8a.
 4. Acompound which is 2-{4[(4aS,8aR)-4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,8,8atetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-acetamide or a hydrate,salt or hydrate of a salt thereof.
 5. A compound which is2-{4-[(4aS,8aR)-4-(3,4-dimethoxphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin1-yl}-acetamidehydrochloride or a hydrate thereof.
 6. A pharmaceutical compositioncomprising a compound of formula I according to claim 1 or apharmaceutically acceptable hydrate, salt or hydrate of a salt thereof,together with a suitable pharmaceutical auxiliary.
 7. A pharmaceuticalcomposition comprising a compound according to claim 2 or apharmaceutically acceptable hydrate, salt or hydrate of a salt thereof,together with a suitable pharmaceutical auxiliary.
 8. A pharmaceuticalcomposition comprising a compound according to claim 3 or apharmaceutically acceptable hydrate, salt or hydrate of a salt thereof,together with a suitable pharmaceutical auxiliary.
 9. A pharmaceuticalcomposition comprising a compound according to claim 4 or apharmaceutically acceptable hydrate, salt or hydrate of a salt thereof,together with a suitable pharmaceutical auxiliary.
 10. A pharmaceuticalcomposition comprising a compound according to claim 5 or apharmaceutically acceptable hydrate thereof, together with a suitablepharmaceutical auxiliary.
 11. A method of treating an airway disorder ina patient comprising administering to a patient in need thereof atherapeutically effective amount of a compound of formula I according toclaim 1 or a pharmaceutically acceptable hydrate, salt or hydrate of asalt thereof, wherein the airway disorder is selected from the groupconsisting of bronchitis, allergic bronchitis, bronchial asthma,emphysema, COPD and allergic rhinitis.
 12. A method of treating anairway disorder in a patient comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of formulaI according to claim 2 or a pharmaceutically acceptable hydrate, salt orhydrate of a salt thereof, wherein the airway disorder is selected fromthe group consisting of bronchitis, allergic bronchitis, bronchialasthma, emphysema, COPD and allergic rhinitis.
 13. A method of treatingan airway disorder in a patient comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of formulaI according to claim 3 or a pharmaceutically acceptable hydrate, salt orhydrate of a salt thereof, wherein the airway disorder is selected fromthe group consisting of bronchitis, allergic bronchitis, bronchialasthma, emphysema, COPD and allergic rhinitis.
 14. A method of treatingan airway disorder in a patient comprising administering to a patient inneed thereof a therapeutically effective amount of a compound accordingto claim 4 or a hydrate, salt or hydrate of a salt thereof, wherein theairway disorder is selected from the group consisting of bronchitis,allergic bronchitis, bronchial asthma, emphysema, COPD and allergicrhinitis.
 15. A method of treating an airway disorder in a patientcomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound according to claim 5 or a hydratethereof, wherein the airway disorder is selected from the groupconsisting of bronchitis, allergic bronchitis, bronchial asthma,emphysema, COPD and allergic rhinitis.